Cardiac mitochondrial function depends on BUD23 mediated ribosome programming
- University of Oxford, United Kingdom
- University of Manchester, United Kingdom
- University of Leeds, United Kingdom
- University of Cambridge, United Kingdom
Abstract
Efficient mitochondrial function is required in tissues with high energy demand such as the heart, and mitochondrial dysfunction is associated with cardiovascular disease. Expression of mitochondrial proteins is tightly regulated in response to internal and external stimuli. Here we identify a novel mechanism regulating mitochondrial content and function, through BUD23-dependent ribosome generation. BUD23 was required for ribosome maturation, normal 18S/28S stoichiometry and modulated the translation of mitochondrial transcripts in human A549 cells. Deletion of Bud23 in murine cardiomyocytes reduced mitochondrial content and function, leading to severe cardiomyopathy and death. We discovered that BUD23 selectively promotes ribosomal interaction with low GC-content 5'UTRs. Taken together we identify a critical role for BUD23 in bioenergetics gene expression, by promoting efficient translation of mRNA transcripts with low 5'UTR GC content. BUD23 emerges as essential to mouse development, and to postnatal cardiac function.
Data availability
RNAseq data have been deposited to ArrayExpress, under the accession code E-MTAB-8673. All proteomics data is included in the supporting files, and raw data have been deposited to PRIDE under the accession code PXD017019.
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Funding
Medical Research Council (MR/L010240/1)
- David Ray
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were carried out in strict accordance with the Animals (Scientific Procedures) Act 1986 (UK) and protocols were approved by an internal ethics committee at the University of Manchester. Every effort was made to minimize suffering. Home office project licence 70/8768 and P3A97F3D1.
Copyright
© 2020, Baxter et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cardiac mitochondrial function depends on BUD23 mediated ribosome programming
eLife 9:e50705.
https://doi.org/10.7554/eLife.50705
